Aminospirocarboalicyclic compounds



06L 25, 1965 MASAHIDE YASAWA ETAL METHOD FOR THE CONTINUOUS TREATMENT OFTEXTI BUNDLES WITH PRESSURE STEAM Filed Nov. 28, 1961 IN VEN TOR.

United States Patent 3,214,470 AMINOSPIROCAREOALICYCLIC COMPOUNDSCharles H. Grogan, Falls Church, Va., assignor to 'h'i- Kem Corporation,Washington, D.C., a corporation of the District of Columbia No Drawing.Filed Aug. 27, 1962, Ser. No. 219,752 8 (llaims. (Cl. 260-563) Thepresent invention relates to novel synthetic organic compounds havingsignificant pharmacological activity and more particularly, to novelaminospiranes and their ring and exo-nitrogen substituted derivatives.

The instant application has a number of significant objects. A primaryobject of the present invention is to provide novel, pharmacologicallyreactive organic compounds characterized by their potent anestheticproperties when administered topically or subcutaneously and which arepotent analgesics when administered systemically.

It is another principal object of the present invention to provide novelaminospiranes and their ring and exo-nitrogen substituted derivatives,as well as the simple acid addition salts of such compounds, all ofwhich have important pharmacological activity.

These and further objects of the present invention will become moreapparent by reference to the ensuing description and appended claims.

Formula 1 illustrates the general structural formula of the novel freebases of the present invention:

In the above formula, the spirane ring system comprises rings A and Bwhich are interconnected by the spiro carbon atom C. Ring A is selectedfrom the group consisting of monoand bicarboalicyclic rings of at least5 atoms. While there is no particular limit on the number of atoms inring A, a ring of 5 to 15 atoms is preferred, such atoms preferably alsobeing carbon atoms. Ring B is a carboalicyclic ring of 5 or 6 atoms(preferably carbon), one of which is substituted by an amino group, saidamino group being at least one ring atom removed from the spiro carbonatom C. The amino group may be a primary amino group (R, R-=H), asecondary amino group (one of R or R=H) or a tertiary amino group(neither R nor R' =H). R and R, in addition to hydrogen, may be one ormore of lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkenyland phenyllower alkyl. Y is at least one substituent on ring A selectedfrom the group consisting of hydrogen, lower alkyl, lower alkenyl, lowercycloalkyl, phenyl, phenyllower alkyl and lower alkoxy, one groupsubstituted on ring B selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower cycloalkyl and phenyllower alkyl. Inthe case of R and R, Y and X, the alkyl and alkenyl groups mostadvantageously contain from 1 to 6 chain atoms (preferably 1 to 3),although there is no upper limit within the framework of the presentinvention to the number of chain atoms in such groups.

In addition to the aminospirane derivatives illustrated by Formula 1,the present invention also contemplates the conversion of suchaminospiranes to their acid addition 3,214,470 Patented Oct. 26, 1965NRR' In Formula 2, all of the elements involved have the samesignificance set forth in the case of the corresponding elements inFormula 1. The new element HA represents the acid used in forming theacid addition salt. HA is a non-toxic acid which may be, for example,hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, succinic,mucic, tartaric, maleic, malic, fumaric, etc. acids. In addition, othernon-toxic acids may be employed in the salt formation so as to obtaindesirable physical properites in the compounds of the present invention,i.e., stability, nonhygroscopicity and solubility, without altering thebasic therapeutic properties of the parent amine.

The compounds of the present invention are extremely valuablepharmacological and medicinal agents. For example, the compound shown inthe illustrative example I is a potent local anesthetic whenadministered locally. The administration of a 1-2.5 aqueous solution ofthe hydrochloride of this amine subcutaneously produces profound localanesthesia with a duration of several hours. Anesthesia of the skin,tongue and other tissues and organs to which the solution may be applieddirectly is rapidly induced and lasts for several hours. In dilutesolution, the substance has a sweet taste when applied to the tongue. Ifa crystal of the solid hydrochloride is applied to the tongue, theimmediate sensation is one of a bitter taste, which gradually becomessweet as the substance dissolves and is dispersed and diluted in theaqueous mixture. In either case, rapid anesthesia is produced whichlasts up to four or more hours, depending upon the amine employed andits concentration. The same sensation of bitterness and sweetness isexperienced with the well-known substance, saccharin, which possesses noanesthetic properties. Saccharin in dilute solution produces an initialsweet taste while the solid form or concentrated solution of the sodiumsalt initially produces a bitter taste.

While the compounds of the present invention are potent localanesthetics when administered topically or subcutaneously, whenadministered systemically their profound pharmacological potency isindeed remarkable. More specifically, the compounds of the presentinvention equal or surpass in potency in the relief of pain thewell-known potent narcotic, meperidine. When administered systemicallyin doses of from 25-150 mg., the compounds of the present invention areextremely potent analgesics.

It is thus evident from the above that the present invention involvesthe discovery of a novel and potent class of extremely eifectiveanesthetics and analgesic compounds.

The compounds of the present invention are conveniently prepared fromthe corresponding spiroketones as illustrated by the following formulae:

1,0 Y Y A c B NHZOH Y Reduction The spiroketone is converted in goodyield into the oxime, which is then reduced to the corresponding primaryamine. The N-substituted amines are obtained by alkylation of theprimary spiroamine or by forming the appropriate amide and reduction ofthe carbonyl group. The derivatives in which either R or R or both aremethyl can also be prepared through the formylation of the primary aminewith formaldehyde or formic acid, following by reduction to theN-substituted methyl derivatives.

Alternatively, the parent primary amines may be obtained by degradativepreparation from the corresponding spiro carboxylic acids by thewell-established procedures of:

(1) Treatment of the spiro carboxylic acid with hydrazoic acid in aninert solvent such as benzene or chloroform in the presence of excesssulfuric acid. This general method is known in the literature and isknown as the Schmidt reaction.

(2) Treatment of the spiro carboxylic acid amide with alkali andhypochlorous or hypobromous acid in aqueous media. This general methodis known in the literature and is known as the Hoflmann degradation.

The following illustrative examples of synthetic procedures involved inobtaining the novel compounds of the present invention are intended tobe illustrative only and are by no means restrictive of the scope of thepresent invention.

Example I .3-amin0spiro [5 .5 undecane (A) The oxime.-Of the severalgeneral methods for converting carbonyl compounds into the correspondingoximes, all consist primarily of heating, or shaking the carbonylcompound with an excess of hydroxylamine hydrochloride and an excess ofbasic substance (such as pyridine, sodium acetate, triethylamine) toliberate the free hydroxylamine in situ in the reaction medium. Thismedium is generally aqueous to which sufficient alcohol may be addedeither to totally dissolve the carbonyl compound at once or to graduallydissolve it as the reaction proceeds. Most of the spiroketones reactrapidly and in good yield in water alone even though they are largelyinsoluble in this substance.

Sixteen and six-tenths grams (0.1 mole) of spiro[5.5]- undecane-B-onewas added to a mixture of grams of sodium acetate and 20 grams ofhydroxylamine hydrochloride dissolved in the minimum of Water at roomtemperature. Although the spiroketone is relatively insoluble in wateror this nearly saturated solution, and no alcohol was added, simplyshaking the mixture for a few minutes resulted in a 95% yield of thecrystalline oxime. The oxime was removed by filtration and washedseveral times with water and dried. It melted at 109-1l0 C. and sharplyat 110 C. on recrystallization from alcohol-water.

In general, most of the other spiroketones gave good yields of thecorresponding oxime by this simple procedure although, in some cases,shaking was continued for several hours on an automatic shaking device.Occasionally, the addition of alcohol facilitated the reaction.

(B) The title amine.The dried oxime was finely powdered and was found tobe sufliciently soluble in anhydrous ether to permit its addition to anexcess of lithium aluminum hydride in anhydrous ether as a solution ineNOH B NRR' c B ether. Some of the oximes were relatively less solublein ether. These were added to the reducing solution of lithium aluminumhydride in ether as a finely powdered suspension or slurry in anhydrousether.

The oxime was stirred for 4 hours in the ethereal lithium aluminumhydride solution. The mixture was then decomposed with water added at arate so as to just maintain gentle reflux of the ether. When allhydrogen had been evolved, a slight excess of water was added and themixture stirred for 4 additional hours and allowed to sit overnight. Theinorganic material was removed by filtration and washed with ether. Theether solution was dried over anhydrous sodium sulfate, the etherstripped off and the residue distilled to yield3-aminospiro[5.5]undecane (B.P. 112 C./12 mm; 88% yield).

(C) The amine hydrochloride.--S0lution of the free amine in anhydrousether and bubbling in gaseous hydrogen chloride gave the hydrochloridesalt which melted at 294-296 C. Recrystallization from methanol-ethergave a product having a melting point of 298-300 C.

Example 11 .N-methyl-3-amin0spir0 [5 .5 undecane (A) Formylationpr0a'uct.8.3 grams (0.05 mole) of the amine of Example I(B) was refluxedfor 4 hours with 4.6 grams of formic acid in 25 ml. of alcohol. Themixture was stripped at the water pump and distilled to yield 7 gm. ofN-formyl-3-aminospiro[5.5]undecane (B.P. 1834 C./5 mm.).

(B) The title amine.Reduction of the formylation product from (A) withlithium aluminum hydride gave the title amine (B.P. 1l2-114 C./9 mm.).

(C) The amine hydrochl0ride.Treatment of the amine with gaseous hydrogenchloride as described in Example I(C) yielded the hydrochloride (M.P.171-2 0).

Example III.-N,N-dimethyl-d-aminospiro[5.511mdecane (A) The titleamine-Reaction of 8.3 gm. (0.05 mole) of the amine from Example I(B)with 12 gm. of formic acid and 12 ml. of concentrated aqueousformaldehyde solution under reflux for 8 hrs. gave 6.3 gm. of the titleamine (B.P. 122-124 C./9 mm.).

(B) The amine hydrochloride-Formed as described under Example I(C) andmelted at 283 C.

Example |IV.N -butyl-3-amin0spiro [5 .5 undecane The amine from ExampleI(B), when reacted with n-butyryl chloride in equimolar quantity in thepresence of a slight excess of 10% sodium hydroxide, yielded then-butyryl amide. The crude amide melted at 7880 C. and was not furtherpurified. It was dried and reduced with lithium aluminum hydride to thetitle amine. The title amine was converted into its hydrochloride salt,which melted at 283-4 C.

Example V.N -benzyl-3 -amin0spir0 [5 .5 undeeane (A) Thebenzamide.-Reacti0n of the free amine from Example I(B) with benzoylchloride as described in Example IV gave the corresponding benzamide(MP. 139- 140 C.).

5 (B) The title amine; hydrchl0ride.Reducti0n of the amide from (A) withlithium aluminum hydride gave the title amine, which was then convertedinto its hydrochloride salt (M.P. 24l-2 C.). This substance was a verypotent local anesthetic.

Example VI.N-(3-chl0r0benzyl )-3-aminospir0 .5

undecane (A) The amide-Reaction of the amine from Example I(B) withm-chlorobenzoyl chloride as described in Example IV gave thecorresponding amine (M.P. 140-141 C.).

(B) The title amine hydrochloride-Reduction of the amide from (A) withlithium aluminum hydride and treatment of the amine with hydrogenchloride gave the title amine as its hydrochloride salt (M.P. 243 4"C.).

Example VII .N- (4-methylbenzyl -3-amin0spir0 [5 .5 1-

undecane (A) The amide-Reaction of the amine from Example I(B) withp-methylbenzoyl chloride as described in Example IV gave thecorresponding amide (M.P. 139- 140 C.).

(B) The title amine hydr0chl0ride.--Reduction of the amide from (A) withlithium aluminum hydride and treatment of the resultant amine withgaseous hydrogen chloride gave the hydrochloride salt of the title amine(M.P. 262-3 C.).

Example VII|I.- 3-amin0spir0 [4.5] decane (A) The oxime.-This oxime wasobtained as illustrated in Example I(A) from spiro[4.5]decane-3-0ne andmelted at 80-82 C. Recrystallization from methanol-water gave a productwith a M.P. of 85-86 C.

(B) The title amine.Reduction of the oxime from (A) with lithiumaluminum hydride gave the title amine (8 gm. from gm. of the oxime) witha B.P. of 88-90 mm mm.).

(C) The title amine hydr0chl0ride.-This was formed as described inExample I(C) and melted at 320-322 C. with decomposition.

Example IX .'9-methyl-3-amin0spiro [5 .5 undecane (A) The 0xime.-Thiswas obtained from 9-methylspiro[5.5]undecane-3-one as described underExample I(A) in 1:1 alcohol-water and melted at 115-l16 C.

(B) The title amine hydrochloride.--Reduction of the oxime from (A) withlithium aluminum hydride gave the title base, which was then convertedinto its hydrochloride salt (M.P. 29l-293 C. with decomposition).

Example X .-3-amin0-4-benzylspir0[4 .5 decane (A) The 0xime.This wasformed as described in Example IX(A) from 4-benzylspiro[4.5]decane-3-oneand melted at 168l69 C.

(B) The title base hydrochloride.Reduction of the oxime from (A) andtreatment of the resultant amine with gaseous hydrogen chloride gave thetitle base hydrochloride (M.P. 278-280 C.).

The procedures set forth above have been illustrated by means of avariety of spiroketones within the framework of the present invention,with variations having been made not only in the spiro structures whichhave previously been defined but in the Y, X, R and R substituents onsaid spiro ring structures. Examples of other spiroketones which may beemployed to obtain the desired products of the present invention include(but are not limited to):

spiro (5.4) decane-Z-one; spiro (4.4 nonane-Z-one 7-methylspiro (4.4nonane 2 one; spiro (6.4 undecane-Z-one; spiro 6.5 dodecane-3-0ne;S-methylspiro (5.4) decane-2- one; 9-rnethylspiro (5.4) decane-Z-one;4-ethyl-9-methylspiro (5.5 undecane-3-one; 9-tert-butylspiro (5.5)undecane-3-one; rnethoxy-spiro (5 .5 undecane-3-one; 9-allyl- 6 spiro(5.5 )undecane-3-one; 9-phenylspiro (5.5 undecane- 3-one;9-cyclohexylspiro(5.5)undecane 3 one; spirotrans-hexahydrohydrindene 2,4cyclohexane-l-one; spiro-trans-Decalin-2,4-cyolohexane-1-one; and spiro-14.4)n0nadecane-2-one.

The formation of N-substituted aminospiranes was illustrated in theexamples by means of butyryl chloride, benzoyl chloride and substitutedbenzoyl chlorides. This method is very widely applicable and a wholevariety of acyl halides may be employed to obtain compounds comingwithin the scope of the present invention. For example, the followingacyl halides are illustrative of those which may be employed to obtainamides that are readily reduced to the desired N-substitutedaminospiranes: acetyl chloride, hexanoyl chloride, phenylpropionylchloride, 4-nitrobenzoyl chloride, diphenylacetyl chloride,4-fluorobenzoyl chloride, tri-methoxybenzoyl chloride, etc.

In addition to the above, still other aminospiranes may be preparedwithin the framework of the present invention. For example, other valuesof R and R include (but are not restricted to): a'llyl; crotyl;cyclohexyl; cyclohexylmethyl; cyclohexenylpropyl; cyclohexenylethyl;phenylethyl; etc. Other values of Y include (but are not restricted to):ethyl; isopropyl; cyclopentyl; benzyl; phenylethyl, ethoxy; ethyl andmethyl (two Ys substituted on ring A); methyl and methyl (two Yssubstituted on ring A); etc. Other values of X include (but are notrestricted to): propyl; methyl; phenylethyl; chlorobenzyl;methoxybenzyl; methylbenzyl; dimethoxybenzyl; allyl; cyclohexyl;cyclohexylmethyl; cyclopentyl; etc.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiment is therefore to be considered in all respects as illustrativeand not restrictive, the scope of the invention being indicated by theappended claims rather than by the foregoing description, and allchanges which come within the meaning and range of equivalency of theclaims are therefore intended to be embraced therein.

What is claimed and desired to be secured by United States LettersPatent is:

1. An aminospirane selected from the group consisting of (1) compoundsof the formula NRR Y wherein A is selected from the group consisting ofmono and bicarboalicyclic rings of at least 5 carbon atoms; B is acarboalicyclic ring of 5 to 6 carbon atoms; NRR is an amino groupsubstituted on ring B in which R and R are selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl,lower cycloalkenyl and phenyl-lower alkyl, said amino group being on .aring carbon atom at least beta to spiro carbon atom C; Y is asubstituent on ring A selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower cycloalkyl, phenyl, phenyl-lower.alkyl and lower alkoxy; and X is a substituent on ring B selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl,phenyl-lower alkyl and lower cycloalkyl; and (2) the therapeuticallyuseful non-toxic acid addition salts of (1).

2. The compounds of claim 1 wherein ring A is composed of 5 to 15 ringatoms.

3. 3-aminospiro(5.5)undecane.

4. N-methyl-3-aminospiro(5.5)undecane.

5. N,N-dimethyl-3-aminospiro(5 .5 undecane.

6. N-.benzyl-3-aminospiro(5.5)undecane.

7. N-(3-chlorobenzy1)-3-aminospi1'o(5.5 )undecane. 8.3-arnino-4-benzylspiro(4.5)decane.

References Cited by the Examiner UNITED STATES PATENTS 2/52 Schwartzmanet a1 260--576 1/54 Woods et a1 260578 XR ume 24, pages 1027-1039(1957).

vWalter, J.A.C.S., volume 74, pages 5186 (1952).

CHARLES B. PARKER, Primary Examiner.

JOSEPH P. BRUST, Examiner.

1. AN AMINOSPIRANE SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS OF THE FORMULA 